X-72567910-C-G

Position:

• chrX-72567910-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The ENST00000373573.9(HDAC8):​c.416G>C​(p.Gly139Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G139R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: HDAC8 ENST00000373573.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.67

Genes affected

HDAC8 (HGNC:13315): (histone deacetylase 8) Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class I of the histone deacetylase family. It catalyzes the deacetylation of lysine residues in the histone N-terminal tails and represses transcription in large multiprotein complexes with transcriptional co-repressors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-72567911-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1064767.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant X-72567910-C-G is Pathogenic according to our data. Variant chrX-72567910-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235479.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC8	NM_018486.3	c.416G>C	p.Gly139Ala	missense_variant	4/11	ENST00000373573.9	NP_060956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC8	ENST00000373573.9	c.416G>C	p.Gly139Ala	missense_variant	4/11	1	NM_018486.3	ENSP00000362674	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

May 11, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	.;.;D;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;.;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.2	.;.;H;.;.;.;.;.;.;.;.;.;.;.;.;.;H;.;.;.;.;.;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.3	.;.;D;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;.;D;.;.;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;.;D;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;.;D;.;.;D;D
Sift4G	Pathogenic	0.0010	.;.;D;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;.;.;D;D
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.90, 0.89, 0.89, 0.86, 0.78, 0.90
MutPred		0.79		Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);.;Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);.;Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);
MVP		0.97
MPC		2.1
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878853048; hg19: chrX-71787760;